tbuckley/cabot-search huggingface dataset:
Abstract 4103: The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer
Authors: Nan Li, Alex Quan, Dan Li, Hua Ren, Weiming Ni, Jing Zhou, Raul Cachau, Mitchell Ho
Journal: Cancer Research (2023)

Abstract Heterogeneous antigen expression is a key barrier influencing the activity of chimeric antigen receptor (CAR) T cells in solid tumors. Here, we developed CAR T cells targeting glypican-1 (GPC1), an oncofetal antigen expressed in pancreatic cancer. We report the generation of dromedary camel VHH nanobody (D4) based-CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We found that a structurally rigid IgG4H and CD28TM domain making the two D4 fragments in proximity drove CAR dimerization, which led to enhanced T cell signaling and tumor regression in orthotopic pancreatic cancer models with low antigen density. Furthermore, single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR-T cells revealed specific genes (e.g., ID1) associated with high T cell polyfunctionality. This study demonstrates the potential of VHH-based CAR-T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes. Citation Format: Nan Li, Alex Quan, Dan Li, Hua Ren, Weiming Ni, Jing Zhou, Raul Cachau, Mitchell Ho. The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4103.
Abstract 3512: Organ-specific effects of <i>Smad4</i> in metastatic pancreatic cancer
Authors: Kaloyan M. Tsanov, Francisco M. Barriga, Yu-Jui Ho, Direna Alonso-Curbelo, Geulah Livshits, Richard Koche, Timour Baslan, Alexandra N. Wuest, Janelle Simon, Sha Tian, Wei Luan, Scott W. Lowe
Journal: Cancer Research (2023)

Abstract Primary and metastatic tumors typically share the same driver gene mutations, but it is unclear if these mutations are functionally relevant across different anatomical sites. Among such mutations, inactivation of the tumor suppressor gene SMAD4 is a hallmark of pancreatic and other gastrointestinal cancers and has been associated with metastatic disease. Here, we develop a mouse model of pancreatic ductal adenocarcinoma that enables Smad4 depletion in the pre-malignant Kras-mutant pancreas and subsequent Smad4 reactivation in late-stage metastatic tumors. Whereas early Smad4 deficiency facilitated tumor formation, later Smad4 restoration had unexpected organ-specific outcomes: no effect on primary tumor growth, suppression of liver metastases, and promotion of lung metastases. Integrative multiomic analysis revealed a near-universal genomic deletion of the Cdkn2a/b locus and organ-specific changes in the tumor cells’ epigenomic state. In particular, the liver and lung differentially favored KLF vs. RUNX dominated chromatin programs, which were confirmed to underpin the divergent effects of Smad4 restoration in functional studies. Our results show how organ-dependent epigenomic changes lead to altered driver gene function in metastatic disease. This organ-specific gene-chromatin interplay may be a generalizable principle in cancer biology and invites a revised paradigm for precision oncology that considers anatomical site in the interpretation of tumor genetics. Citation Format: Kaloyan M. Tsanov, Francisco M. Barriga, Yu-Jui Ho, Direna Alonso-Curbelo, Geulah Livshits, Richard Koche, Timour Baslan, Alexandra N. Wuest, Janelle Simon, Sha Tian, Wei Luan, Scott W. Lowe. Organ-specific effects of Smad4 in metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3512.
Abstract 368: Neutralizing antibody against GDF-15 restores cachexia
Authors: Feng He, Hao Peng, Jianhui Li, Li Ding, Feng Hao, Jinying Ning, Guojin Wu
Journal: Cancer Research (2023)

Abstract Growth and differentiation factor 15 (GDF-15) is an attractive target for the treatment of cachexia. Ponsegnomab is such a therapeutical antibody in the clinical trial. Here, we developed a humanized GDF-15 neutralizing antibody (KA1641-ZY1) with better efficacy than ponsegnomab in the pre-clinical experiments. KA1641-ZY1 had high affinity to GDF-15 (KD=0.05nM), with cross-reacting to monkey GDF15. KA1641-ZY1 neutralized GDF-15 in the culture medium and disrupted GDF-15-induced GFRAL signaling more efficiently than Ponsegnomab in reporter cell assay (IC50=0.13nM vs. 0.21nM). In a mouse model with exogenous GDF15 protein-induced body decrease, KA1641-ZY1 restored body weight by giving as low as 5ug/kg while ponsegnomab failed. In the HT1080, Colo 205, and LS513 xenograft tumor-induced cachexia mouse models, KA1641-ZY1 restored the body weight decrease with 0.3mg/kg while ponsegnomab restored the weight with higher than 1mg/kg. In addition, KA1641-ZY1 also restored cisplatin-induced body decrease in GDF15 humanized mice. It has no detectable non-specific binding to red blood cells, neutrophils, PBMCs, and HUVEC cells, with a half-life of about nine days in the mouse. These results suggest that KA1641-ZY1 is a potential candidate drug for cachexia. Citation Format: Feng He, Hao Peng, Jianhui Li, Li Ding, Feng Hao, Jinying Ning, Guojin Wu. Neutralizing antibody against GDF-15 restores cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 368.
Abstract 1569: OXC-101 kills cancer by disturbing microtubule polymerization and inhibiting MTH1
Authors: Ulrika Warpman Berglund, Helge Gad, Kumar Sanjiv, Ann-Sofie Jemth, Oliver Mortusewics, Lars Brautigam, Juha Rantala, Thomas Helleday
Journal: Cancer Research (2023)

Abstract Many cancers suffer from replication stress, oxidative stress, a dysfunctional redox status, and high levels of endogenous oxidative DNA damage. OXC-101 (karonudib, TH1579) targets these vulnerabilities by stopping the cancer cells in mitosis, generating ROS which increases oxidative stress and oxidative DNA damage, thereby killing the cancer cells. The aim of this study was to further investigate the underlying mechanism of OXC-101 and the cancer specific effects in solid cancers. Using e.g. microtubule polymerization assays, co-immunoprecipitation and immunofluorescence microscopy, we show a dual mechanism of action of OXC-101, disturbing microtubule function and inhibiting the nucleotide pool sanitizing enzyme MTH1. Furthermore, we demonstrate the importance of a functional spindle assemble checkpoint (SAC) for the response of OXC-101, since knocking down MAD2,using siRNA, or inhibiting SAC with reversine, results in treatment resistance. We show that the excess of oxidized nucleotides is cytotoxic when inhibiting or knocking out MTH1 in zebrafish embryos, and that pretreatment with ROS scavenger rescues the effect of OXC-101 in cancer cells. These data indicate that the increased incorporation of oxidized nucleotides into DNA is, together with the mitotic arrest, an important part of the mechanism of action and response. OXC-101 has a broad anti-cancer effect. In an ex vivo drug sensitivity study of 157 primary biopsies from solid cancer patients, OXC-101 was efficacious in a large proportion of the patient derived samples, with best responses in endometrial (73%), HNSCC (73%), bladder (70%) and prostate (83%) cancer samples. Biomarker searches for genetic alterations explaining responders/non-responders are presently on-going. In summary, the dual mechanism of action of the mitotic MTH1 inhibitor OXC-101 explains its strong anti-cancer effect. Citation Format: Ulrika Warpman Berglund, Helge Gad, Kumar Sanjiv, Ann-Sofie Jemth, Oliver Mortusewics, Lars Brautigam, Juha Rantala, Thomas Helleday. OXC-101 kills cancer by disturbing microtubule polymerization and inhibiting MTH1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1569.
Abstract 4349: C-C chemokine receptor 2-positive monocytic myeloid-derived suppressor cells predicts chemotherapeutic responses of the metastatic lesions in breast cancer patients
Authors: Ju Won Kim, Jason K. Sa, Seung Pil Jung, Kyong Hwa Park, Serk In Park
Journal: Cancer Research (2023)

Abstract Anti-tumoral T cell immunity is counterbalanced by several types of immunosuppressive cells such as Myeloid-Derived Suppressor Cells (MDSC). Circulating MDSC levels correlate with poor prognosis and metastatic progression of breast cancer patients. However, the value of MDSC in predicting chemotherapeutic treatment responses in the metastatic lesions is not clearly understood. We performed a prospective cohort clinical study to measure MDSC before and after chemotherapy in metastatic breast cancer patients (N=64). Multicolor flow cytometry was used to quantitate two major subtypes, i.e. monocytic (M-) and polymorphonuclear (PMN-) MDSC, and one additional subtype, C-C chemokine receptor 2 (CCR2)-positive M-MDSC in the fresh peripheral blood mononuclear cells. M-MDSC were defined as HLA-DRlow/−CD45+CD11b+CD15−CD14+ PBMC, and PMN-MDSC were defined as CD45+CD11b+CD33+CD15+ CD14− PBMC. PMN-MDSC and CCR2+ M-MDSC, but not M-MDSC, were significantly increased after chemotherapy. Subsequently, we divided the patients by two groups (therapy-sensitive vs. -resistant groups) by treatment responses. Treatment-resistant patients had significantly increased CCR2+ M-MDSC. Unsupervised clustering of patients based on MDSCs populations dichotomized patients PMN-MDSC high or M-MDSC high groups. M-MDSC high patients had increased bone and lymph node metastasis. In addition, CCR2+ M-MDSC levels correlated with the progression-free survival (P&amp;lt;0.05). Altogether, our results showed that CCR2+ M-MDSC levels potentially predict the therapeutic responses in the metastatic lesions of breast cancer patients. Citation Format: Ju Won Kim, Jason K. Sa, Seung Pil Jung, Kyong Hwa Park, Serk In Park. C-C chemokine receptor 2-positive monocytic myeloid-derived suppressor cells predicts chemotherapeutic responses of the metastatic lesions in breast cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4349.
Abstract 5508: Artesunate increases enzalutamide efficacy in advanced prostate cancer
Authors: Xinyi Wang, Fengyi Mao, Jinghui Liu, Yifan Kong, Dang he, Chi Wang, Zhiguo Li, Xiaoqi Liu
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is the most diagnosed worldwide. PCa development and progression require androgen receptor (AR) signaling, which stimulates its downstream gene expressions and cancer progression. While second-generation anti-androgen drugs plus androgen deprivation therapy (ADT) remains the first-line treatment for advanced prostate cancer patients, around one-third of patients will relapse in a short period. Advanced prostate cancer results in more mortalities than primary PCa patients. Evidence shows that the recurrence is caused by AR overexpression, AR variants, AR mutations, and signaling crosstalk. Thus, it is urgently needed to discover a novel therapeutic strategy for treating advanced prostate cancer. The heat shock protein family (HSP), including HSP90 and HSP70, play important roles in refolding aggregated protein for cancer cell proteomic equilibrium. HSP is induced primarily by heat shock factor (HSF1). As AR’s chaperone protein, HSP70 and HSP90 increase AR transcription activity. Inhibiting HSP70 and HSP90 promotes STUB1, an E3 ligase, binding to AR and AR - V7, and ubiquitination. Artesunate (ART) is a semi-synthetic ingredient from Artemisia annua and is the most common treatment for malaria throughout the world. It was approved for medical use by the FDA (Food and Drug Administration) (Food and Drug Administration). Recently ART has been unveiled for its anticancer properties. However, the efficacy of ART treatment in advanced prostate cancer and the direct target of ART have not been investigated yet. Herein, we have examined the efficacy of combining Enzalutamide (Enza) and ART in advanced prostate cancer cell lines. We also performed unbiased bioinformatics analysis using RNA seq results in enzalutamide-resistant cell line C4-2R cells and 22RV1 cells to investigate the cell response toward ART treatment. We identified ART could downregulate of AR signaling pathway. Moreover, we determined that ART treatment induces AR degradation in proteasome dependent manner. Interestingly, we found HSP70 and HSP90 are also decreased in RNA seq results. Taking these together suggests that ART may target HSF1 directly. Our results suggest ART induced AR degradation could be a promising clinical strategy for advanced prostate cancer. Citation Format: Xinyi Wang, Fengyi Mao, Jinghui Liu, Yifan Kong, Dang he, Chi Wang, Zhiguo Li, Xiaoqi Liu. Artesunate increases enzalutamide efficacy in advanced prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5508.
Abstract 6124: Recombinant apurinic/apyrimidinic endonuclease-1/redox factor-1 plus acetylsalicylic acid combination therapy inhibits tumorigenesis in an orthotopic xenograft murine model of triple-negative breast cancer
Authors: Yu Ran Lee, Hee Kyoung Joo, Eun-Ok Lee, Sungmin Kim, Hao Jin, Yeon Hee Choi, Eun Ju Choi, Byeong Hwa Jeon
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is characterized with hormone receptor negative and frequently exhibits inherently aggressive clinical behavior, resulting in poor prognoses. TNBCs are highly heterogenic, leading to obstacles in identifying new therapeutic targets and performing targeted therapy. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1), a multifunctional protein, is mainly involved in DNA repair and redox regulation; it is upregulated in various cancers and is extracellularly secreted because of hyperacetylation. We previously reported that hyperacetylation induced APE1/Ref-1 release causes apoptosis in TNBCs. In the current study, we aimed to assess the therapeutic efficacy of combination treatment involving recombinant human APE1/Ref-1 (rhAPE1/Ref-1) plus acetylsalicylic acid (ASA) in TNBC xenograft mice. ASA co-treatment was used to induce and lasting acetylation of rhAPE1/Ref-1. For in vivo analysis, we constructed an orthotopic xenograft in vivo model of TNBC by using MDA-MB-231 cells. We performed combination therapy involving intravenous injection of purified rhAPE1/Ref-1 (1 mg/kg) and oral administration of ASA (20 mg/kg) thrice a week for 6 weeks in TNBC xenograft mice. This rhAPE1/Ref-1 plus ASA combination therapy inhibited tumor formation and growth, without damaging liver or kidney tissue, and decreased plasma levels of the cancer marker CEA and breast cancer-specific markers CA27-29 and CA15-3 in the TNBC xenograft mice. The TNBC group, which underwent combination therapy, had more apoptotic cells and greater inflammatory cell infiltration in tumor tissues than the vehicle group did. Additionally, in tumor tissue of TNBC with combination therapy exhibits increased apoptosis following upregulation of Bax, cleaved-caspase-3, and cleaved-PARP. Thus, we found that rhAPE1/Ref-1 plus ASA combination therapy enhanced antitumor effects in TNBCs via inflammatory cell infiltration and apoptosis signaling pathways. Our findings indicate the therapeutic potential of rhAPE1/Ref-1 plus ASA combination therapy for TNBC. Citation Format: Yu Ran Lee, Hee Kyoung Joo, Eun-Ok Lee, Sungmin Kim, Hao Jin, Yeon Hee Choi, Eun Ju Choi, Byeong Hwa Jeon. Recombinant apurinic/apyrimidinic endonuclease-1/redox factor-1 plus acetylsalicylic acid combination therapy inhibits tumorigenesis in an orthotopic xenograft murine model of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6124.
Abstract 6031: KYNU upregulation is a prominent feature of NRF2-activated cancers and is associated with tumor immunosuppression and poor prognosis
Authors: Ricardo A. Leon Letelier, Ali H. Abdel Sater, Yihui Chen, Ranran Wu, Jennifer B. Dennison, Soyoung Park, Ehsan Irajizad, Hiroyuki Katayama, Jody Vykoukal, Samir Hanash, Edwin J. Ostrin, Johannes F. Fahrmann
Journal: Cancer Research (2023)

Abstract Activation of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, either through gain-of-function mutations in the NRF2 encoding gene NFE2L2 or through loss-of-function of its suppressor, Kelch-like ECH-associated protein 1 (KEAP1), is a frequent manifestation in various malignancies. NRF2 activation exerts pro-tumoral effects in part by altering cancer cell metabolism. We previously reported a novel mechanism of NRF2 tumoral immune suppression through selective upregulation of the tryptophan metabolizing enzyme kynureninase (KYNU) in lung adenocarcinoma. In the current study, we explored the Pan-Cancer relevance of NRF2-mediated KYNU upregulation. We analyzed the gene expression dataset for 9,801 tumors representing 32 cancer types in The Cancer Genome Atlas (TCGA). Elevated KYNU expression levels paralleled increased gene-based signatures of NRF2-activation and was strongly associated with an immunosuppressive tumor microenvironment, marked by high expression of gene-based signatures of Tregs as well as immune checkpoint blockade-related genes CD274 (PDL-1), PDCD1 (PD-1), and CTLA4, regardless of cancer type. Cox proportional hazard models further revealed that increased tumoral KYNU gene expression was prognostic for poor overall survival in several cancer types, including thymoma, acute myeloid leukemia, low grade glioma, kidney renal papillary cell carcinoma, gastric adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC). Using PDAC as a model system, we confirmed that siRNA-mediated knockdown of NRF2 reduces KYNU mRNA expression, whereas activation of NFE2L2 (the encoding gene for NRF2) through either small molecule agonists or siRNA-mediated knockdown of KEAP1 upregulated KYNU. Metabolomic analyses of conditioned media from PDAC cell lines revealed elevated levels of KYNU-derived anthranilate, confirming KYNU as enzymatically functional. Collectively, our findings highlight the multi-cancer relevance of the NRF2-KYNU axis and of tumoral KYNU as a prognostic marker of poor overall survival associated with immunosuppression. Citation Format: Ricardo A. Leon Letelier, Ali H. Abdel Sater, Yihui Chen, Ranran Wu, Jennifer B. Dennison, Soyoung Park, Ehsan Irajizad, Hiroyuki Katayama, Jody Vykoukal, Samir Hanash, Edwin J. Ostrin, Johannes F. Fahrmann. KYNU upregulation is a prominent feature of NRF2-activated cancers and is associated with tumor immunosuppression and poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6031.
Abstract 2925: <i>In vitro</i> characterization of next generation therapeutic antibodies
Authors: Benita Quist, Hamed Janbazacyabar, David Cobeta Lopez, Namrata Jayanth, Gemma Moiset
Journal: Cancer Research (2023)

Abstract Therapeutic antibodies are an established drug class. Checkpoint inhibitors, such as anti-PD-1/PD-L1 and anti-CTLA-4 antibodies for cancer indications, and anti-TNF-α monoclonal antibody against autoimmune disorders represent some of most successful therapeutics in the past decade. Over 100 therapeutic targets suitable for antibody therapy have been identified for various disease indications, with several currently in late-stage clinical trials. In addition, there has been an explosion in the various types of therapeutic antibody modalities due to the increasing number of antibody engineering platforms. The new emerging bi-specific T-cell engaging antibodies (BiTEs) along with antibody-drug conjugates (ADCs) have demonstrated superior therapeutic qualities over the traditional monoclonal antibodies. Here, we describe a pipeline to extensively characterize the various antibody therapeutics in vitro utilizing multiple innovative technologies. Assays to determine target expression and binding potency provide a thorough understanding of the target engagement. Furthermore, we present data from an innovative technology platform, the z-Movi, which measures cell avidity to predict invitro effector functions of T-cell engaging therapies, enabling more robust read-outs and could drive the lead selection of said therapies. Several mechanisms of action of different antibodies were investigated and relevant case studies describing the innate immune effector functions and the signaling pathway modulation are presented. Using a unique label-free approach, the xCELLigence, we report on the kinetics of target cell killing mediated by lymphocytes upon recognition of antigen-antibody complexes. Finally, safety assessment studies focusing on on-target/off-tumor effects of antibodies on primary cells were conducted. The cytokine profiling and cell viability assays to assess potential risk due to exaggerated levels of cytokine, reiterate the specificity and safety of the next generation of antibody therapeutics and support Investigational New Drug (IND) applications. In conclusion, we provide a comprehensive report on the in vitro characterization of the advanced antibody therapeutics, showcasing a pipeline for development and functional characterization of various antibody modalities, including bispecific T-cell engagers. This workflow can be used to progress a wide range of engineered antibodies from pre-clinical to the clinical phase of the drug discovery process. NJ and GM contributed equally to the work. Citation Format: Benita Quist, Hamed Janbazacyabar, David Cobeta Lopez, Namrata Jayanth, Gemma Moiset. In vitro characterization of next generation therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2925.